Abstract
INTRODUCTION: Dendritic cells (DCs) play a crucial role in the recovery following acute kidney injury (AKI). Fms-related tyrosine kinase 3 ligand (Flt3L) is essential for the generation and maintenance of DCs. However, the cellular source of Flt3L in the kidney and its contribution on renal DC function during AKI remain unclear. METHODS: An online available dataset and specimens collected from AKI patients were used to analyze FLT3L expression. Wild type (WT) mice, T cell-deficient (Tcra(KO)), and type 1 conventional DC (cDC1)-deficient (Irf8(KO)) mice underwent ischemia-reperfusion (IR) injury to induce AKI. These mice were treated with either mouse recombinant Flt3L (rFlt3L) or the Flt3 inhibitor gilteritinib. In vitro experiments with human and murine bone marrow (BM) cells, HK-2 cell line, Jurkat T cells, the monocyte cell line THP1, CD4(+) T cells and cDC1s were conducted to validate the link between Flt3L and DCs. RESULTS: Circulating FLT3L levels were significantly elevated in patients with AKI. This correlated with the degree of kidney dysfunction observed in these patients. Flt3L was expressed in and released by tubular epithelial cells, with minimal expression in immune cells. Flt3L primarily promoted the activation and expansion of cDC1s and polarization of CD4(+)T cells in vitro, an effect that was blocked by dephosphorylation of AKT and ERK signaling with gilteritinib. In vivo, gilteritinib worsened the outcomes after AKI by decreasing kidney cDC1 expansion. Conversely, therapeutic administration of rFlt3L promoted renal cDC1 accumulation and improved kidney function in mice with AKI. However, in Irf8(KO) mice, rFlt3L failed to improve outcomes. CONCLUSION: Flt3L is upregulated in both humans and mice during IRI-induced AKI and is likely produced by tubular epithelial cells. It mainly promotes the expansion and activation of kidney cDC1 cells, thereby reducing the severity of AKI in mice. These findings suggest that Flt3L-dependent, cDC1-targeted immunotherapy could be a promising strategy for treating AKI.